PROJECT SUMMARY Nucleic acid-sensing (NA)-TLRs, particularly the TLR7 and TLR9, play a fundamental role in the development of lupus and deletion or inhibition of NA-TLR signaling has been shown to have therapeutic efficacy. Recent studies have elucidated the mechanism by which NA-TLRs traffick from the endoplasmic reticulum to the endolysosomal compartment where they provide signals to activate cells and the immune system. This project will investigate the role of endosomal transporters that appear to be necessary for NA-TLR signaling. These endosomal complex are part of a intracellular trafficking system required for the biogenesis and function of lysosome-related organelles. Deficiency of these complexes are linked to a rare recessive disorder, Hermansky-Pudlak syndrome. This project will study the role HPS genes in TLR signaling and autoimmunity looking specifically at AP-3, BLOC-1 to-3. This will be accomplished by defining the role of these gene in the development of lupus (aim1), defining the role of AP-3 in TLR signaling in B cells (aim 2), and defining how these four genes function in TLR transport and signaling (aim 3). By accomplishing these aims, this project will provide a comprehensive view of the role of LRO biogenesis in endosomal TLR signaling of autoantibody- relevant immune cells and in the development of lupus, by studying the whole animal, immune function, and at the cellular levels. These studies are relevant to SLE and will provide an increased understanding of the disease pathogenesis with the possibility of applying this information to the bedside.